1. Cell line and patient-derived xenograft models reveal elevated CDCP1 as a target in high-grade serous ovarian cancer
- Author
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Anna V. Tinker, Donal J. Brennan, Mark N. Adams, Jermaine Coward, Catherine Kennedy, Niara Oliveira, Brittney S. Harrington, Christopher Flatley, Elizabeth A Beaven, Claire M. Davies, Naven Chetty, Anna deFazio, Catherine Shannon, Yaowu He, Deborah K Roche, Brian Gabrielli, Jane E. Armes, A.J. Crandon, C. Blake Gilks, John D. Hooper, Lewis Perrin, and S J Wallace
- Subjects
0301 basic medicine ,Cancer Research ,Pathology ,medicine.medical_specialty ,patient-derived xenograft ,CDCP1 ,SKOV3 ,CUB-domain containing protein 1 ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Antigens, CD ,Antigens, Neoplasm ,Cell Movement ,Cell Line, Tumor ,high-grade serous ovarian cancer ,Biomarkers, Tumor ,medicine ,Animals ,Humans ,Neoplasm ,RNA, Small Interfering ,Cell Proliferation ,Ovarian Neoplasms ,Cell growth ,business.industry ,Cancer ,medicine.disease ,Survival Analysis ,Cystadenocarcinoma, Serous ,Neoplasm Proteins ,3. Good health ,Disease Models, Animal ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,Monoclonal ,Cancer research ,Heterografts ,Immunohistochemistry ,Female ,Neoplasm Grading ,Translational Therapeutics ,Ovarian cancer ,business ,Cell Adhesion Molecules ,Clear cell - Abstract
Background: Development of targeted therapies for high-grade serous ovarian cancer (HGSC) remains challenging, as contributing molecular pathways are poorly defined or expressed heterogeneously. CUB-domain containing protein 1 (CDCP1) is a cell-surface protein elevated in lung, colorectal, pancreas, renal and clear cell ovarian cancer. Methods: CUB-domain containing protein 1 was examined by immunohistochemistry in HGSC and fallopian tube. The impact of targeting CDCP1 on cell growth and migration in vitro, and intraperitoneal xenograft growth in mice was examined. Three patient-derived xenograft (PDX) mouse models were developed and characterised for CDCP1 expression. The effect of a monoclonal anti-CDCP1 antibody on PDX growth was examined. Src activation was assessed by western blot analysis. Results: Elevated CDCP1 was observed in 77% of HGSC cases. Silencing of CDCP1 reduced migration and non-adherent cell growth in vitro and tumour burden in vivo. Expression of CDCP1 in patient samples was maintained in PDX models. Antibody blockade of CDCP1 significantly reduced growth of an HGSC PDX. The CDCP1-mediated activation of Src was observed in cultured cells and mouse xenografts. Conclusions: CUB-domain containing protein 1 is over-expressed by the majority of HGSCs. In vitro and mouse model data indicate that CDCP1 has a role in HGSC and that it can be targeted to inhibit progression of this cancer.
- Published
- 2016
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